Abstract

The gene encoding the nuclear receptor hepatocyte nuclear factor 4 (HNF4) generates isoforms HNF41 and HNF47 from usage of alternative promoters. In particular, HNF47 is expressed in the pancreas whereas HNF41 is found in liver, and mutations affecting HNF4 function cause impaired insulin secretion and/or hepatic defects in humans and in tissue-specific 'knockout' mice. HNF41 and 7 isoforms differ exclusively by amino acids encoded by the first exon which, in HNF41 but not in HNF47, includes the activating function (AF)-1 transactivation domain. To investigate the roles of HNF41 and HNF47 in vivo, we generated mice expressing only one isoform under control of both promoters, via reciprocal swapping of the isoform-specific first exons. Unlike Hnf4 gene disruption which causes embryonic lethality, these '7-only' and '1-only' mice are viable, indicating functional redundancy of the isoforms. However, the former show dyslipidemia and preliminary results indicate impaired glucose tolerance for the latter, revealing functional specificities of the isoforms. These 'knock-in' mice provide the first test in vivo of the HNF4 AF-1 function and have permitted identification of AF-1-dependent target genes.